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2-Year Old With No Ventilatorequirement but Who Cannot Be Extubated

obert Little, MD

A 2-year-old boy was intubated during treatment for pneumonia. After resolution of theinfection, he had no pulmonary requirement for ventilation and could function without itwhile awake. When he slept, however, he would have decreasing respiratory effort,increasing hypercapnia, and episodic apnea. This report provides an example of late-onsetcongenital central hypoventilation syndrome.Semin Pediatr Neurol 15:157–159 © 2008 Elsevier Inc. All rights reserved.

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2-year-old boy presented to an outside hospital with a1-week history of cough. He was diagnosed with pneu-

onia and admitted for observation. Overnight, he had anncreasing oxygen requirement. He later had an episode ofpnea and was intubated. He was then transferred to a chil-ren’s hospital for further evaluation and treatment.His past medical history was significant for bronchiolitis at 6

eeks of age. He was intubated and remained on mechanicalentilation for 2 weeks. He had mild global developmental de-ays. He was receiving physical, occupational, and speech ther-pies. He was making progress with these therapies, and thereas no regression in his development. His father had a history of

ebrile seizures, but there was no family history of developmen-al delays or pulmonary problems.

His initial hospital course was unremarkable. He remainedfebrile, and he was slowly weaned from mechanical ventila-ion. He was extubated on the third day of hospitalization.owever, he had an episode of apnea several hours later andas again intubated. Over the next several days, he failed

xtubation multiple times. With each attempt, he did wellmmediately after extubation. He had a good respiratory ef-ort, and blood gas measurements before extubation wereormal. After several hours, he had decreasing respiratoryfforts despite increasing hypercarbia, and he had episodes ofpnea when he fell asleep.

Physical examination was unremarkable. His chest waslear to auscultation with no wheezes. He was intubated, bute opened his eyes spontaneously and followed commandsasily. Cranial nerves II-XII were intact. He had good muscleone and strength in all extremities. Deep tendon reflexesere normal in all extremities.

rom Phoenix Children’s Hospital, Phoenix, AZ.ddress reprint requests to Robert Little, MD, Phoenix Children’s Hos-

pital, 1919 E Thomas Road, Phoenix, AZ 85016. E-mail: rlittle@

nphoenixchildrens.com

071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.spen.2008.09.004

The initial diagnostic workup included magnetic reso-ance imaging of the brain and cervical spine and an electro-ncephalogram, which were normal. He was given broncho-ilators and steroids with no clinical changes. He was given arial of pyridostigmine with no obvious clinical benefit. DNAnalysis of the PHOX2B gene revealed a polyalanine repeatxpansion mutation of 25 repeats in 1 allele and 20 repeatsnormal) in the other allele. This confirmed the diagnosis ofongenital central hypoventilation syndrome (CCHS).

A tracheostomy was performed, and he was transitioned to aentilator suitable for home use. At the time of hospital dis-harge, he was able to breathe independently while awake, bute needed mechanical ventilation whenever he was asleep.

iscussionCHS was first described in 1970.1 It is a rare syndromeharacterized by hypoventilation, which is often present onlyuring sleep. The initial reports of this syndrome were exclu-ively in neonates. After the gene responsible for CCHS wasdentified, however, there were some cases reported in olderhildren and adults. These cases were termed late-onsetCHS. Although late-onset CCHS is very rare, it is important

o recognize the clinical signs and symptoms to establish theiagnosis and provide appropriate care.The term Ondine’s curse was used in some of the early

escriptions of this syndrome. The term has been used toescribe a number of medical conditions involving a loss ofespiratory control and is not specific to CCHS. For theseeasons, the term should not be used to describe CCHS.2

The American Thoracic Society published formal diagnos-ic criteria for CCHS in 1999.3 According to these criteria, theyndrome is characterized by alveolar hypoventilation,hich is usually present only during sleep, particularly dur-

ng nonrapid eye movement sleep. Patients with CCHS were

oted to have diminished or absent response to hypercarbia

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158 R. Little

nd hypoxia. The diagnosis could only be made in the ab-ence of primary pulmonary, cardiac, or neuromuscular dis-ase or an identified brainstem lesion. Other conditions areften found in association with CCHS, including Hirsch-prung disease and tumors of neural crest origin, most com-only neuroblastoma. Also, a number of signs of autonomicysfunction are seen, such as a lack of heart rate variability,oor temperature regulation, diminished papillary light re-ponse, and feeding difficulties. However, these associatedonditions are not necessary for the clinical diagnosis ofCHS.3 These American Thoracic Society criteria stated thatCHS was a syndrome that typically was seen in the newborneriod. The authors noted that some patients may present

ater in infancy, but there was no discussion of this syndromeresenting beyond infancy.The genetic basis for CCHS was first found in 2003.4 The

ene, Phox2b, is located on chromosome 4p12 and codes fortranscription factor. It was previously identified as a possi-le gene involved in Hirschsprung disease. Most cases are deovo mutations, but several families have been identifiedith multiple affected members across several generations.5

n familial cases, the syndrome is inherited in an autosomalominant pattern. Some family members have mutations inhe Phox2b gene with no obvious clinical manifestations.6

The most commonly identified mutation in patients withCHS is a polyalanine repeat expansion within exon 3. This

eads to 25 to 33 polyalanine repeats in the expressed protein.he normal number of repeats is 20. This mutation accounts

or more than 90% of the identified cases of CCHS, but aariety of other mutations in the Phox2b gene have beeneported.6 There is a correlation between the number of poly-lanine repeats and the clinical severity of the symptoms.atients with only 25 repeats (as the patient reported above)ay show a milder course or later onset. Some of the individuals

dentified in familial cases who are asymptomatic also have only5 repeats. The number of repeats also correlates with the num-er of symptoms of autonomic dysfunction.7 Once the geneesponsible for CCHS was identified, the number of reportedases increased; however, it remains a rare condition, with sev-ral hundred reported cases worldwide.7 Most of the time, theiagnosis is made in the newborn period. A number of cases of

ate-onset CCHS have been reported, including some patientsho were identified as adults.8

Mutations in Phox2b have been identified in some patientsith neuroblastoma. Some familial forms of neuroblastomaave been associated with mutations in Phox2b but not theolyalanine repeat seen in CCHS.9,10 These patients did notave any respiratory difficulties or other signs of CCHS. Aecent case series described 15 children with a new syndromeharacterized by rapid-onset obesity, hypoventilation, andutonomic dysfunction.11 Although the phenotype seemsery similar to late-onset CCHS, none of the children in thiseport had mutations in the Phox2b gene, suggesting that thiss a genetically distinct syndrome. These children typicallyad onset of symptoms in the first 10 years of life. The me-ian age of onset of obesity was 3 years, with other featureseveloping later.The previously published clinical criteria for CCHS stated

hat the diagnosis can only be made in the absence of any c

dentified brainstem lesion.3 However, 2 patients were re-ently reported with CCHS and typical Phox2b mutationsho also had brainstem abnormalities seen on magnetic res-nance imaging.12 The phenotype for Phox2b mutations mayherefore be more varied than reported to date.

The function of the Phox2b gene product in humans is notnown. However, studies of the mouse homolog of this geneave provided a great deal of information that may explainhe clinical features of CCHS. The gene is highly conservedetween mice and humans. Phox2b is expressed in thehombencephalon early in the development of the mouserain, and it is essential for the development of motor neu-ons in the hindbrain.13 Mice with Phox2b mutations do notespond normally to hypercapnea and have central apnea.14

ice with these mutations also show reduced response toentral hypoxia.15 Stornetta et al16 showed that Phox2b ispecifically expressed in neurons in the retrotrapezoid nu-leus of the mouse brainstem that serve as central chemosen-ors in respiratory pathways. Phox2b is not expressed in theentral respiratory column caudally. They concluded thatespiratory dysfunction as a result of a Phox2b mutationould therefore only occur during times when breathing wasependent on central chemical drive, which may explainhy hypoventilation usually occurs during sleep in CCHS.16

Expression of Phox2b is essential but not sufficient for theevelopment of cholinergic neurons in mice.17 Phox2b is ex-ressed in neural crest cells during mouse brain development. Itegulates the development of sympathetic neurons,18 and it ismportant in regulating the development of many autonomiceflex pathways.19 Phox2b also is involved in the regulation ofxpression of tyrosine hydroxylase and tyrosine kinase20 as wells dopamine beta-hydroxylase21 in central and peripheral nor-drenergic neurons. Mice lacking Phox2b expression do notorm sympathetic or parasympathetic enteric ganglia.22

None of the data described previously have been shown inumans, but these studies provide a good understanding of howutations in Phox2b can lead to the observed clinical manifes-

ations of CCHS. Phox2b is critical in the development of hind-rain respiratory centers, and it is likely that it plays a similar role

n humans, which explains the central hypoventilation. It is anmportant regulator of noradrenergic expression and the devel-pment of autonomic pathways in mice. Again, a similar role isikely in humans, easily explaining the observed autonomic dys-unction in CCHS. Finally, it is known that Phox2b is expressedn neural crest cells. Although the link between this and tumorsf neural crest origin is less clear, it has been shown in mice andumans that mutations of the Phox2b gene are associated withevelopment of these tumors.Currently, the treatment for CCHS is supportive care. Pa-

ients usually require tracheostomy and mechanical ventila-ion for support of respiration. Some patients may need aentilator only while asleep, but many of them require somessistance while awake. For patients who need respiratoryupport while awake, diaphragmatic pacing may be an op-ion to allow for greater mobility.3,23

onclusionCHS remains a rare clinical entity. However, the genetic

haracterization of this syndrome has allowed for increased

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A 2-year-old who cannot be extubated 159

ecognition and improved diagnosis. Further identificationf patients with Phox2b mutations will allow for a better un-erstanding and refinement of the phenotype of this geneticondition. Although the majority of patients with CCHSresent in the newborn period, there are a number of peopleho do not manifest symptoms until much later in life. The

ecognition of the typical clinical features of this syndromeay allow for more prompt diagnosis and treatment.

eferences1. Mellins RB, Balfour HH Jr, Turino GM, et al: Failure of automatic

control of ventilation (Ondine’s curse). Medicine 49:487-504, 19702. Nannapaneni R, Behari S, Todd NV, et al: Retracing “Ondine’s curse”.

Neurosurgery 57:354-363, 20053. American Thoracic Society: Idiopathic congenital central hypoventila-

tion syndrome: Diagnosis and management. Am J Respir Crit Care Med160:368-373, 1999

4. Amiel J, Laudier B, Attie-Bitach T, et al: Polyalanine expansion andframeshift mutations of the paired-like homeobox gene PHOX2B incongenital central hypoventilation syndrome. Nat Genet 33:459-461,2003

5. Doherty LS, Kiely JL, Deegan PC, et al: Late-onset central hypoventila-tion syndrome: A family genetic study. Eur Respir J 29:312-316, 2007

6. Berry-Kravis EM, Zhou L, Rand CM, et al: Congenital central hypoven-tilation syndrome: PHOX2B mutations and phenotype. Am J RespirCrit Care Med 174:1139-1144, 2006

7. Weese-Mayer DE, Berry-Kravis EM: Genetics of congenital central hy-poventilation syndrome: Lessons from a seemingly orphan disease.Am J Respir Crit Care Med 170:16-21, 2004

8. Antic NA, Malow BA, Lange N, et al: PHOX2B mutation-confirmedcongenital central hypoventilation syndrome: Presentation in adult-hood. Am J Respir Crit Care Med 174:923-927, 2006

9. van Limpt V, Chan A, Schramm A, et al: Phox2B mutations and theDelta-Notch pathway in neuroblastoma. Cancer Lett 228:59-63, 2005

0. Bourdeaut F, Trochet D, Janoueix-Lerosey I, et al: Germline mutationsof the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.Cancer Lett 228:51-58, 2005

1. Ize-Ludlow D, Gray JA, Sperling MA, et al: Rapid-onset obesity with

EDITORIAL CO

itions that, although not intuitively obvious at first, turn out

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hypothalamic dysfunction, hypoventilation, and autonomicdysregulation presenting in childhood. Pediatrics 120:e179-e188,2007

2. Bachetti T, Robbiano A, Parodi S, et al: Brainstem anomalies in twopatients affected by congenital central hypoventilation syndrome. Am JRespir Crit Care Med 174:706-709, 2006

3. Pattyn A, Hirsch M, Goridis C, et al: Control of hindbrain motor neurondifferentiation by the homeobox gene Phox2b. Development 127:1349-1358, 2000

4. Dubreuil V, Ramanantsoa N, Trochet D, et al: A human mutation inPhox2b causes lack of CO2 chemosensitivity, fatal central apnea, andspecific loss of parafacial neurons. Proc Nat Acad Sci U S A 105:1067-1072, 2008

5. Ramanantsoa N, Vaubourg V, Dauger S, et al: Ventilatory response tohyperoxia in newborn mice heterozygous for the transcription factorPhox2b. Am J Physiol Regulatory Integrative Comp Physiol 290:R1691-R1696, 2006

6. Stornetta RL, Moreira TS, Takakura AC, et al: Expression of Phox2b bybrainstem neurons involved in chemosensory integration in the adultrat. J Neurosci 26:10305-10314, 2006

7. Huber K, Ernsberger U: Cholinergic differentiation occurs early inmouse sympathetic neurons and requires Phox2b. Gene Expression13:133-139, 2006

8. Huber K, Karch N, Ernsberger U, et al: The role of Phox2B in chromaf-fin cell development. Dev Biol 279:501-508, 2005

9. Dauger S, Pattyn A, Lofaso F, et al: Phox2b controls the development ofperipheral chemoreceptors and afferent visceral pathways. Develop-ment 130:6635-6642, 2003

0. de Pontual L, Nepote V, Attie-Bitach T, et al: Noradrenergic neuronaldevelopment is impaired by mutation of the proneural HASH-1 gene incongenital central hypoventilation syndrome (Ondine’s curse). HumMol Genet 12:3173-3180, 2003

1. Adachi M, Browne D, Lewis EJ: Paired-like homeodomain proteinsPhox2a/Arix and Phox2b/NBPhox have similar genetic organizationand independently regulate dopamine beta-hydroxylase gene tran-scription. DNA Cell Biol 19:539-554, 2000

2. Pattyn A, Morin X, Cremer H, et al: The homeobox gene Phox2b isessential for the development of autonomic neural crest derivatives.Nature 399:366-370, 1999

3. Ali A, Flageole H: Diaphragmatic pacing for the treatment of congenitalcentral alveolar hypoventilation syndrome. J Pediatr Surg 43:792-796,

2008

MMENT

ow that the gene responsible for the disease I used toknow as Ondine’s curse is known, we are learning lots

f interesting things about the pathophysiology of the condi-ion and the cellular mechanisms involved. Perhaps the mosturprising revelation is the fact that the disease is associatedometimes with Hirschsprung disease and the identificationf evidence of more widespread autonomic dysfunction inatients with both congenital central hypoventilation syn-rome and Hirschsprung disease. I suspect that as we learnore about other diseases in which apnea is a characteristic

eature (eg, Joubert syndrome and Athabaskan brainstemysgenesis), we will begin to understand that disturbed de-elopment of the chemoreceptor centers in the brainstem is,rst, frequently only a part of a larger array of autonomicbnormalities and, second, can manifest in a variety of symp-oms that were not obviously linked before. It is clear nowhat Athabaskan brainstem dysgenesis is also the result ofutations of genes important in the development of the

rainstem (HOXA-1).1 Undoubtedly, there will be other con-

o be related to aberrations of the development of brainstemuclei.2 It also seems likely that mutations in genes that pri-arily act during brainstem development will be found toave effects on the development of central nervous systemtructures remote to the brainstem nuclei.3

John Bodensteiner, MDBarrow Neurological Institute

St Joseph’s Children Health CenterPhoenix, AZ

eferences. Tischfield MA, Bosley TM, Salih MA, et al: Homozygous HOXA1 muta-

tions disrupt human brainstem, inner ear, cardiovascular and cognitivedevelopment. Nat Genet 37:1035-1037, 2005

. Rodier PM, Ingram JL, Tisdale B, et al: Embryological origin for autism:Developmental anomalies of the cranial nerve motor nuclei. Comp Neu-rol 370:247-261, 1996

. Bosley TM, Alorainy IA, Salih MA, et al: The clinical spectrum of ho-mozygous HOXA1 mutations. Am J Med Genet A 146A:1235-1240,

2008